PROJECT SUMMARY: The long-term objective of the Paul B. Beeson Emerging Leaders Career Development Award in Aging (K76) is to support the development of the candidate into a leading physician-scientist in translational neuroscience of Aging and Alzheimer's disease (AD). The proposed K76 award will enable the candidate to develop the skills necessary to design and conduct multi-modal scientifically rigorous studies to advance our understanding of the pathophysiology of Aging and AD that will have a significant impact in the field. This overall objective will be accomplished through a structured, supervised research experience along with formal didactic instruction focused on (1) neurobiology of aging, AD, and glutamatergic neural systems, (2) structural brain analysis with electron microscopy, (3) genomics and (4) leadership development. AD is a serious public health concern associated with significant morbidity and mortality. There is a compelling need for studies that offer the possibility to advance the neurobiological understanding of AD and aging, which is AD's major risk factor, and the development of novel targets and more effective treatments. The neural circuits affected in aging and in AD are similar, involving the glutamatergic connections among cortical areas and with the hippocampal formation. In aging, synaptic changes occur with minimal neuronal death while in AD, there is frank loss of neurons. With the goal of further understanding the susceptibility of glutamatergic neural circuits to aging and AD that culminates in cognitive decline, the proposed project utilizes a multi-dimensional investigative approach focusing on the major glutamate transporter in the brain, EAAT2. EAAT2 plays a critical role in determining glutamate levels synaptically and extrasynaptically, and regulating physiological glutamatergic neurotransmission, that all are critical for learning, memory, and synaptic health. Importantly, EAAT2 activity is significantly decreased in both aging and AD, and associated with neurodegeneration in the latter. This proposal investigates EAAT2's pathophysiological role in aging and AD by, first, quantifying changes at the synaptic level, with correlative behavioral assays, and gene expression profiles in aging and AD mouse models, and second, with an intervention with an EAAT2-enhancer, the glutamate modulator riluzole. Moreover, this proposal uses a newly developed conditional EAAT2 knock-out (KO) mouse for further mechanistic studies on EAAT2's impact on gene expression patterns and behavior in the aging brain. These integrated aims will delineate the biology of EAAT2 in aging and AD brains at the structural, molecular and functional levels and will test EAAT2 enhancement as a therapeutic target for age- related cognitive decline and AD. This proposal builds on PI's recent work on glutamatergic dysregulation in the vulnerable excitatory synapses in aging and AD, her outstanding leadership skills and on the very extensive experience by mentors in structural brain analysis (such as electron microscopy), neurobiology of aging, AD, and glutamatergic neural systems. The applicant has assembled a preeminant and complementary group of mentors with the relevant expertise, including Professors Bruce McEwen, John Morrison, Patrick Hof and Paul Rosenberg, to guide her research project, and to supervise her career development and training activities. In summary, the proposal utilizes a multimodal and integrative investigative approach to test an innovative mechanistic hypothesis that can ultimately result in identification and validation of novel targets and development of effective treatments to age-related cognitive decline and AD, which remain thus far unmet medical needs. Importantly, the skills and data acquired during the K76 award period will provide the candidate with the tools required to achieve the long-term goal of becoming an independent and leader investigator in translational neuroscience research of aging and AD.